Typically in the drug industry, drug products exist in two dosage forms, solid and liquid dosage forms. Included in the solid dosage forms are tablets, pellets, pills, beads, spherules and so on. These solid dosage forms are often coated for various reasons, such as odour or taste masking, protection from moisture, light and/or air, prevention from destruction by gastric acid or gastric enzymes, enhanced mechanical strength, aesthetics and controlled release including controlling release sites and/or release rate.
At present, the commercially used technology for coating solid dosage forms is the liquid coating technology. Generally, a mixture of polymers, pigments and excipients is dissolved in an appropriate organic solvent (for water insoluble polymers) or water (for water soluble polymers) to form a solution, or dispersed in water to form a dispersion, and then sprayed onto the dosage forms and dried by continuously providing heat, typically using hot air, until a dry coating film is formed.
The liquid coating processes and equipment have been well established and widely adopted by the pharmaceutical industry. Typical liquid coating is carried out in a rotary pan coater for larger size solid dosages such as tablets, or in a fluidized bed coater for smaller size dosage forms such as pellets or pills.
The liquid coating technique can give an exceptionally uniform smooth lustrous coating surface. However, the inherent disadvantages caused by using organic solvents or water have become increasingly obvious and unacceptable by the pharmaceutical industry. These include vaporizing organic solvents or water which is extremely energy consumptive. This adds considerable cost to the coating cost and long processing time is unavoidable.
In order to obtain a uniform smooth coating surface, temperature is regulated to prevent too fast a vaporizing rate which leads to formation of large pores. Furthermore, liquid coating feed rate needs also to be controlled to allow evaporation of the sprayed liquid so that the tablets do not become soaked in the liquid. The liquid spray cannot be too fast, to allow the evaporation of the sprayed liquid. If too much liquid is sprayed (than can be evaporated, the whole thing may become soaked. Therefore long processing time up to hours and even days is necessary for liquid coating to dry. Using organic solvents results in environmental pollution, solvent recycling cost and operation dangers of explosion.
Organic solvents add another cost to the coating cost in addition to the huge energy consumption and long processing time. From the viewpoint of cost and environment, usage of water in place of organic solvents is highly beneficial. However, evaporation of water still needs longer processing time and consumes much energy. In addition, enormous amount of hot air, especially in the case of a fluidized bed coater, is required to maintain the temperature of the coater and entrain the vapours out of the system. Because all air must be cleaned before and after the coater, the air treatment system adds significant cost to the entire system.
In order to overcome these limitations of liquid coating, new efforts have been made in recent years to develop a new technology based on powder coating, which is often termed as “dry coating” in the pharmaceutical coating fields.
The basics of dry coating include spraying of a mixture of finely ground particles of polymer and other materials onto the solid dosage surface without using any solvent, and then heating the dosages in a curing oven until the coating powder mixture is fused into a coating film on the dosage surface. Compared with traditional liquid coating, dry coating is highly valued for energy and time saving, high utilization of the coating material, long storage duration, environmental friendliness, safety, thereby resulting in low overall operation costs. To date, three dry coating processes have been developed in this area of technology. However, they are seen to have various shortcomings which limit them from becoming commercialized.
The first prior-art dry coating technique is based on the usage of plasticizers. This technique will be referred to as “plasticizer-dry-coating”. Plasticizers, the majority of which are liquid organic chemicals with small molecular weight, are often added to lower the softening temperature (Ts) or glass transition temperature (Tg) of thermoplastic polymers, allowing film formation at a reduced temperature and improving the flexibility and tensile strength of the obtained film. The plasticizer is retained within the polymer and attenuates the attractive forces between the polymer chains to give flexibility during the whole life of the film. Ts or Tg decreases with the increase of plasticizer/polymer ratio. When plasticizer/polymer ratio is increased to an extent that the reduced Ts or Tg is close to or below the room temperature, the polymer film will become sticky and soft, having no practical values.
For solid dosage coating, low Ts or Tg of the film-forming polymer is essential to protect active ingredients in the dosages from being damaged at a high temperature which necessitates the use of plasticizers. In the prior-art plasticizer-dry-coating technique, powdered materials are sprayed onto a dosage surface simultaneously with spraying the plasticizer. The sprayed liquid plasticizer would wet the powdered particles and the dosage surface, promoting the adhesion of the particles to the dosage surface. Both the powder materials and plasticizer are sprayed by means of compressed air through separate nozzles. The coated dosages are then cured in an oven for a predetermined time above Tg or Ts of the polymer, forming a continuous film.
There are several prior arts mainly from two groups that reported the plasticizer-dry-coating. One group, Pearnchob et al., coated pellets with micronized ethylcellulose particles, Eudragit RS particles (a copolymer of methacrylic acid ester and trimethylammonioethyl methacrylate chloride) and shellac in a fluidized bed by means of the plasticizer-dry-coating technique (Pearnchob N, Bodmeier R. “Coating of pellets with micronized ethylcellulose particles by a dry powder coating technique”, International J Pharmaceutics, 2003, 268:1-11; Pearnchob N, Bodmeier R. “Dry powder coating of pellets with micronized Eudragit RS for extended drug release”, Pharmaceutical Research, 2003, 20: 1970-1976; Pearnchob N, Bodmeier R. “Dry polymer powder coating and comparison with conventional liquid-based coatings for Eudragit RS, ethylcellulose and shellac”, European J Pharmaceutics and Biopharmaceutics, 2003, 56:363-369). The other group, Obara et al., used the same technique to coat tablets in a pan coater and beads in a fluidized bed with hydroxypropyl methylcellulose acetate succinate (HPMCAS) (Obara S, Maruyama N, Nishiyama Y, et al. “Dry coating: an innovative enteric coating method using a cellulose derivative”, European J Pharmaceutics and Biopharmaceutics, 1999, 47: 51-59).
FIG. 1 is a schematic diagram of a Prior-Art electrostatic coating apparatus for solid dosage forms wherein disclosed in US 2002/0034592 A1 in which 10 is a tablet feeding chute; 12. 12′ are rotary drums; 16, 16′ are electrostatic spraying guns; 18, 18′ are trays to hold particles; 20, 20′ are infrared ray heaters; 22: tablet collection chutes; A (A′) are preconditioning stations; B (B′) are coating stations; C (C′) are fusing stations.
FIG. 2 is a schematic diagram of a Prior-Art heat-dry-coating apparatus and process for tablet coating disclosed by Cerea M et al. wherein (1) rotating disk; (2) infrared lamp; (3) powder feeder; (4) temperature probe; (5) coating tablets; (6) glass cover.
The effects of plasticizer types and concentration and curing temperatures on the film forming ability of polymers, surface morphology and controlled release profiles of the obtained coats have been investigated in some of the above listed references. Both Pearnchob and Obara indicated that the coating thickness or coating level (coating level is referred to as the weight gain based on the uncoated dosage weight) could be regulated by the amount of plasticizer feeding, a much larger amount of plasticizer being required for the adhesion of more particles to the dosage surface in order to gain a coat with enough thickness for sufficient protection, gastric resistance or proper controlled release.
Adversely for this technique, the wetting force is the only force for adhering the particles onto the dosage surface, and only the wetted particles could adhere onto the dosage surface. As a result, excessive plasticizer is required to wet sufficient amount of particles and then gain enough coat thickness. However, the excessive plasticizer reduces Ts or Tg of the polymer close to or less than room temperature, leading to a very soft and sticky film, which is a lethal defect of this technique and cannot be accepted by the pharmaceutical coating. Moreover, the weak and non-directional wetting force alone is difficult to give a uniform and smooth coating surface.
Another prior-art dry coating technique, here referred to as “electrostatic-dry-coating”, is derived from the successfully and widely used electrostatic coating technique in metal finishing.
There are two electrostatic coating processes for the metal finishing industry: electrostatic spraying and electrostatic fluidized bed coating, among which electrostatic spraying is the most common process used for application of powder coatings in metal finishing.
The basic principle of electrostatic spraying concerns propulsion of the dry powder by means of compressed air through a spray gun, in which it becomes electrically charged and then moves and adheres to the earthed substrate surface. The movement of the particles between the charging gun and the substrate is governed by a combination of electrical and hydrodynamic forces. The electrical forces are derived from the repulsion force between the charged particles and the electrostatic attraction between the charged particles and earthed substrate, while the hydrodynamic forces are produced by the air that blows the powder towards the substrate from the spray gun.
The following describes the steps for the charged powder particles to adhere to the substrate surface. First, charged particles are uniformly sprayed onto the earthed substrate by virtue of hydrodynamic forces and electrostatic attractions. As the spraying proceeds, the charged particles attracted onto the substrate surface repel each other due to carrying the same charges, which advantageously induces a uniform and even distribution of particles on the substrate surface, hence producing a uniform coating. When there are enough particles accumulated on the substrate that the repulsion force of the deposited particles against the coming particles reaches and exceeds the electrostatic attraction of the earthed substrate to the coming particles, particles cannot adhere to the substrate any more. At this point, the coating thickness can hardly increase any more, which provides an approach for controlling the coating thickness.
Therefore a successful electrostatic spraying should satisfy several requirements: a powder charging/dispensing unit, an earthed conductive substrate and powdered particles able to be charged.
There are two types of spraying units, generally in the form of guns, classified into corona charging guns and tribo charging guns according to their charging mechanism. Corona charging guns are characterized by electrical breakdown and thereafter ionization of air by imposing a high voltage on a sharp pointed needle-like electrode in the gun, the powder particles picking up the negative ions on their way from the gun to the substrate. Tribo charging guns make use of the principle of frictional charging associated with the electrical properties of solid materials.
Electrostatic coating of solid dosage forms with powdered materials, i.e. electrostatic-dry-coating, is more difficult than coating of metals due to the much weaker electrical conductivity of solid dosage forms than metal substrates. For metal substrates, the sufficiently strong electrostatic attraction between the charged particles and the grounded metal substrate can cause particles to firmly adhere to the substrate surface, producing a coat with a desirable thickness. For solid dosage forms, however, the electrostatic attraction between the charged particles and the solid dosages with weak conductivity or high electric resistance is typically weak, leading to difficulty in producing a thick coat. Despite this difficulty, the more uniform coating produced by electrostatic coating in comparison with the “plasticizer-dry-coating” has been encouraging researchers to devote efforts to overcome this difficulty of the electrostatic-dry-coating. Most of such efforts are exclusively directed to designing special apparatus to fulfill coating solid dosage forms by electrostatic-dry-coating.
US 2003/0138487 A1 (Continuation of U.S. Ser. No. 08/966,582, or PCT/GB96/01101), US 2002/0034592 A1 (Continuation of U.S. Ser. No. 09/629,439), and US 2002/0197388 A1 (Continuation of U.S. Ser. No. 09/310,741) provide an apparatus for electrostatically coating pharmaceutical tablets with powdered coating materials. The apparatus includes two occluding rotary drums, two electrostatic spray guns, two infrared ray-based fusion stations, two cooling stations, a tablet feeding chute and a tablet collection chute (shown in FIG. 1). The special design aims at increasing the electrostatic attraction between the particles and tablets by making every tablet effectively grounded, and at greatly improving the coating efficiency by directing and restricting the charged particles onto the tablet surface without spraying onto the surroundings. However, the apparatus is far from being commercially applicable because it is too complicated thereby leading to operational complications, and completely different from the conventional coating apparatus such as pan coaters and fluidized beds used in liquid coating. Moreover, in order to speed up the coating process, a high fusion temperature (or curing temperature) of above 130° C. or even up to 250° C. seems indispensable since no plasticizer is used in this technique, which may cause a great harm to the coating material as well as the active ingredients, especially for the case where the coating material contains active ingredients.
US 2003/0211229 A1 describes another apparatus based on a photoconductive drum, by which charged powder material is applied to a photoconductive drum, transferred to an intermediate belt and then to a solid dosage form.
All the above mentioned publications on electrostatic-dry-coating focus on new apparatus designs for effective coating of powdered materials on tablets but not making use of the existing apparatus, attempting to improve the electrostatic attractions and thereafter the coating efficiency.
Unfortunately, the increased coating efficiency has been compromised by the complicated coating apparatus, which does little good in cost efficiency to pharmaceutical factories that prefer to accept dry coating operated in a simpler coating apparatus or in their present apparatus such as pan coaters for liquid coating of tablets with few modifications. In addition, all those work focused on tablet coating. No work has been reported on the dry coating of smaller dosage forms such as beads. Those beads are currently coated by liquid spraying in fluidized bed which requires even more hot air to fluidize the particles than a liquid coating pan coater.
The high curing temperatures needed for curing are known to damage the active ingredient in the dosages or coating materials such as those disclosed in US 2003/0138487 A1 (Continuation of U.S. Ser. No. 08/966,582, or PCT/GB96/01101), US 2002/0034592 A1 (Continuation of U.S. Ser. No. 09/629,439), and US 2002/0197388 A1 (Continuation of U.S. Ser. No. 09/310,741) and which may produce fragile coats.
The third dry coating technique was reported most recently by Cerea M et al (Cerea M, Zheng W, Young C, et al. “A novel powder coating process for attaining taste masking and moisture protective films applied to tablets”, International J Pharmaceutics 2004, 279:127-139). In this reported technique, only heat was used to realize the dry coating of tablets, so that it may be referred to as “heat-dry-coating”. In this coating technique, Eudragit E PO (a copolymer based on dimethylaminoethyl methacrylate and methacrylates) particles were continuously spread onto the tablets contained in a lab-scale spheronizer by way of a motorized single screw powder feeder, with an infrared lamp positioned on the top of the spheronizer as a heating source, without using any solvent and plasticizer (see FIG. 2). Powder adhesion onto the tablet surface is promoted only by the partially melted polymer that generates binding forces between the particles and between the particles and tablet surfaces. Because Eudragit E PO has a low Tg of about 50C and because the film of Eudragit E is sufficiently elastic, coating with Eudragit E generally requires no plasticizers.
However, for the above reported “heat-dry-coating”, the coating material used, Eudragit E, is a special example, which does not require plasticizer, so that this coating process does not apply to those polymers requiring plasticizers. In addition, it is also very hard to get a smooth, uniform and thick coating only by the help of the said heat-based adhesion.
Therefore, it would be very advantageous to provide a method and apparatus for direct coating solid dosage forms using powdered materials which overcomes the aforementioned difficulties.